Since being reported as a possible treatment for schizophrenia in the late 1930s, pentylenetetrazole (PTZ) has been used as a therapy for a variety of maladies and conditions involving the central nervous system, such as senile confusion, depression, vertigo, and so forth, as well as being used as a circulatory and respiratory stimulant and cough suppressant. PTZ has the following formula:

PTZ is known by tradenames and synonyms including METRAZOL, CARDIAZOL pentetrazol, among others. In 1982 the U.S. Food and Drug Administration withdrew its approval for marketing of PTZ in the United States and required that evidence be provided for efficacy in support of claims made for PTZ used alone or in combination with other agents. See 47 Federal Register 19208 (May 4, 1982).
PTZ is believed to block or reduce passage of ions through the ion channel associated with type A gamma-aminobutyric acid (GABAA) receptors. GABA is the major inhibitory neurotransmitter in the central nervous system. GABA, in the absence of PTZ and other channel blockers, GABAA receptor antagonists and/or allosteric modulators, binds to the GABAA receptor leading to receptor channel opening and passage of chloride ions through the channel.
Recent work has shown that administration of PTZ can lead to improvement in learning and memory. For example, in a transgenic mouse model of Down syndrome, daily doses of PTZ generated improvements in learning lasting months after mice were last exposed to PTZ. See, e.g., Fernandez et al., 2007 Nature Neuroscience 10(4):411-413; Rueda et al., 2008, Neuroscience Letters 433(1):22-27; and U.S. Patent Application Publication. No. 2008/0009475, published Jan. 10, 2008, which disclosures are incorporated herein by reference in their entireties for all purposes.
Peak concentration of PTZ in blood generally occurs within 10 minutes after intravenous (IV) or intraperitoneal (IP) delivery. PTZ has high bioavailability after oral dosing (PO), and peak blood levels generally occur within approximately 30 to 60 minutes when PTZ is given orally. PTZ readily crosses the blood brain barrier. It has a relatively short plasma half-life of about 60 minutes. Following administration to mice, rats, dogs, humans and other living systems, PTZ undergoes oxidative metabolism, a key determinant for PTZ's short half-life. There are a number of metabolites that have been characterized for PTZ, at least 2 of these are oxidized variants of PTZ and account for over 60% of the eliminated product. These metabolites are 6-hydroxypentetrazole and 8-hydroxypentetrazole. Oxidation is likely carried out by enzymes of the cytochrome P450 superfamily.
Increasing dosing frequency or dosage amounts of PTZ in therapeutic applications to compensate for its relatively short half-life in vivo requires careful consideration in view that its side effects, including seizures and convulsions, are Cmax driven. PTZ may also cause dose-dependent, significant inhibitory effects on the activity of metabolic enzymes including CYP450 and other members of this superfamily, which could potentially be detrimental when, for instance, PTZ is co-administered with other drugs.
New therapies having a therapeutic benefit similar or improved to that of PTZ are sought. Included in such sought-after therapies would be, for instance, compounds exhibiting a half-life in vivo longer than that for PTZ.